Ménétrier’s Disease and Its Atypical Presentation in Four Siblings

Ménétrier’s disease is a rare, acquired, premalignant disorder of the stomach distinguished by hypertrophic giant mucosal folds in the proximal part of the stomach (body and fundus), diminished acid secretion and excessive mucous production, resulting in hypoalbuminemia. Menetrier’s is also known as hypoproteinaemic hypertrophic gastropathy and giant hypertrophic gastritis. We present a case of four siblings who presented between 2010 and 2017 with symptomatic iron deficiency anaemia or upper gastrointestinal symptoms with confirmed Ménétrier’s disease. The etiology of Ménétrier’s disease is unknown but it has been linked to raised TGF- α (transforming growth factor alpha protein) in the gastric mucosa causing increased signalling of epidermal growth factor. It is also associated with infections such as cytomegalovirus and Helicobacter pylori . Despite these associations, there have been cases without any of these viruses detected. Diagnosis is usually made by barium swallow or endoscopic evaluation, which characteristically shows thickened gastric folds, while the biopsies' hallmark feature is massive foveolar hyperplasia. We present a case series of four siblings who presented between 2010 and 2017 with symptomatic iron deficiency anaemia or upper gastrointestinal symptoms with confirmed Ménétrier’s disease.


Introduction
Rare conditions such as Ménétrier's disease are not always the first thing on a clinician's mind when constructing a differential diagnosis for iron deficiency anaemia (IDA) or upper gastrointestinal (UGI) symptoms. The pathophysiology of this disease is still unknown, but it has been hypothesised that increased transforming growth factor alpha (TGF-α) up-regulation is the underlying mechanism of cellular changes in the gastric mucosa [1]. It has been noted that enormous secretions of this mucus and TGF-α contribute toward gastric hypertrophy [2]. Ménétrier's disease has been associated with human cytomegalovirus (HCMV) infection in children and Helicobacter pylori infection in adults [3].

Case Presentation
We present a case series of four sisters who presented between 2010 and 2017 with either UGI symptoms (abdominal pain, bloating, acid reflux, haematemesis, and vomiting) or with symptomatic IDA, which were refractory in nature despite multiple iron infusions. The father of these siblings had died of stomach and throat malignancy.
The eldest sister presented in 2010 at the age of 32, with symptomatic refractory IDA. She had an extensive past medical history of recurrent miscarriages secondary to lupus anticoagulant positivity, recurrent pulmonary embolisms, chronic kidney disease, and pulmonary hypertension. The second sister also presented in 2010 at the age of 31, but with symptoms of upper abdominal pain, nausea, and vomiting.
The third sister attended the emergency department of the same hospital around the same year at the age of 22, with abdominal pain, nausea, vomiting, and haematemesis. Her past medical history consisted of depression and recurrent miscarriages. During her inpatient admission, she had a barium swallow and gastroscopy which confirmed the suspected diagnosis of Ménétrier's disease. The youngest sister presented in 2017 at 25 years of age, as a referral from the IDA clinic. She complained of recurrent abdominal pain, bloating, and nausea post-prandially.
Laboratory studies of all siblings revealed IDA, but other biochemical indices, such as liver function tests, urea and electrolytes, C-reactive protein, and coagulation screen were unremarkable. This is somewhat unusual in Ménétrier's disease, as it has also been noted in other similar cases that this disease often presents with features consistent with a protein-losing gastropathy, namely hypoalbuminemia and widespread oedema [4].
All siblings underwent gastroscopy and gastric biopsy. The youngest sibling's endoscopy was performed with and without blue dye for better visualisation of the thickened gastric folds (Figure 1). The histology revealed hallmark features of prominent foveolar hyperplasia and mild focal glandular dilatation. There was also oedema, mild chronic inflammation, and patchy glandular loss. The barium swallow of the third sister showed gross gastric abnormalities with thickened mucosal folds, suggestive of Ménétrier's disease ( Figure 2). 2022

FIGURE 2: Barium swallow test image of the third sister
Barium swallow test result is depicting thickened mucosal folds (black arrows).
The youngest sibling also had a contrast-enhanced computed tomography (CECT) of the thoracoabdominal-pelvic region which revealed abnormal thickening of the wall of the stomach with particularly remarkable enlargement of the rugal folds involving the cardia, body, and antrum in continuity. The pylorus was relatively spared. Appearances were suggestive of Ménétrier's disease ( Figure 3). The clinical course of the disease varied between the four siblings. The eldest sister had escalating requirements for iron infusions and due to recurrent symptoms associated with her condition, she underwent gastrectomy in 2011, with the aim of symptom control and mitigating the potential of future malignant transformation. Unfortunately, this patient passed away from respiratory failure, unrelated to Ménétrier's disease. The second eldest sister and the youngest sister have been referred onwards to tertiary centres for further management of their conditions. The second sister was referred onward due to refractory abdominal pain. The third sister is currently still being symptomatically treated locally. The youngest sister despite treatment with regular iron infusions, annual endoscopies, and a trial of long-acting octreotide remained iron deficient.

Discussion
Our report is a unique example that the presentation of all four siblings with Ménétrier's disease could be a sign that this is an inherited condition. There has been a link that people with this condition are at high risk of acquiring gastric tumours such as adenocarcinomas and lymphomas [5]. This is particularly pertinent as their father died from a gastric malignancy. Another peculiarity of our case is that the four sisters presented without hypalbuminaemia and without gastric colonisation with H. pylori or CMV infection, which is dissimilar to many other case reports available in the literature [6]. Most reports suggest that H. pylori may be a contributor toward the development of foveolar hyperplasia and gastric hypertrophy, rather than a direct causative agent [7]. Some articles suggest albumin levels can be normal in Ménétrier's disease, despite this being a commonly accepted diagnostic criterion for the condition [6]. In our case, the serum albumin level of the patients was always within normal range without any associated oedema, and this remained the same throughout their documented clinical progress.
The pathophysiology of Ménétrier's disease was discerned from transgenic mice studies, who were found to have raised TGF-α in the gastric mucosa. It is thought that these stimulate epidermal growth factor receptors (EGFR), which are usually found mainly in the hypertrophied foveolar gastric mucosa [2]. There have been very few papers that suggest a genetic component to Ménétrier's disease, our report of four sisters displays that there is a suggestion of this disease being inherited.
This disease normally presents with epigastric pain, nausea, vomiting, early satiety, oedema, diarrhoea, weakness, anorexia, and gastrointestinal bleeding [4]. The disease is progressive and has a predisposition to the male gender with the average age of diagnosis being middle-aged, between 40 and 60 years [4]. The disease typically involves the whole fundus, body, and upper part of the gastric mucosa, with the sparing of the antrum [8].
Diagnosis of Menetrier's is made by X-ray imaging following a barium meal or by endoscopic evaluation. Endoscopy with deep mucosal biopsy is required to establish the diagnosis and exclude other differentials of thickened gastric folds [4]. Other tests such as 24-hour pH monitoring, chromium-labelled albumin tests, and serum gastrin levels can be performed, the validity of which may be less reliable if the patient is on proton pump inhibitor (PPI) therapy. Expected findings in Ménétrier's disease would encompass the following; 24-hour pH monitoring would reveal hypochlorhydria, chromium-labelled albumin test would show increased GI protein loss and serum gastrin level would be normal. Histologically, the most characteristic feature is massive foveolar hyperplasia (hyperplasia of surface and glandular mucous cells). The glands are elongated with a corkscrew-like appearance and cystic dilation is common [3].
Large folds within the stomach are not seen only in Ménétrier's disease but can be seen in other conditions, such as Zollinger-Ellison syndrome, malignancies, infection (CMV, histoplasmosis, syphilis, tuberculosis), and infiltrative disorders such as sarcoidosis [9]. All the sisters in our case study had negative serology for CMV and syphilis. They all had negative quantiferon tests excluding tuberculosis and angiotensinconverting enzyme (ACE) levels were normal excluding sarcoidosis. These results with the histology results lead to our diagnosis of Ménétrier's disease.
Management of Ménétrier's disease is complex and includes various therapeutic options. Many studies have mentioned positive results with H. pylori eradication using proton pump inhibitors and antibiotics [10]. In H. pylori-negative cases, some evidence suggests that somatostatin analogues such as octreotide help in relieving symptoms, but it is unknown if this has an effect on the progression of the disease or development of malignancies [11].
Anticholinergics have also been used to decrease protein loss. A high-protein diet should be recommended for patients with low levels of albumin to replace protein loss. It has been noted that in chronic cases, cetuximab has been shown to be effective in treating Ménétrier's disease. Cetuximab, a monoclonal antibody targeted against epidermal growth factor receptor (EGFR), has been used in the treatment of the condition [12]. In cases of severe disease refractory to optimal medical treatment, laparoscopic subtotal gastrectomy can be considered [13].
It is of utmost importance to conduct regular surveillance of Ménétrier's disease patients due to their increased risk of developing into gastric adenocarcinoma or lymphoma or any other features consistent with malignant transformation [14]. Patients should be notified about the possibility of cancer in Ménétrier's disease and that the definitive treatment is either a partial or total gastrectomy [15].

Conclusions
Thickened gastric folds are commonly seen at gastroscopy with a broad differential diagnosis. Ménétrier's disease should be considered as a potential diagnosis when a patient is found to have thickened gastric folds, particularly in patients with a strong family history, such as this cohort. The aetiology, pathogenesis, and treatment of this condition are currently poorly understood and therefore its medical management is extremely challenging. If appropriate, family screening could be considered in first-degree relatives when an individual is diagnosed with this condition. Our case series are as far as we are aware, the first published report that involves four siblings, it demonstrates the possibility of a genetic link or the plausibility of associated conditions, from which some members of this family suffered, which may have predisposed them to the development of this condition.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.